The energy demands of the retina are some of the highest in the body. Glucose is metabolized to satisfy this demand, but is not thought to be the primary substrate used by retinal neurons. Instead, lactate derived from glial cells is thought to be an important energy source. This hypothesis is supported by the unique pattern of monocarboxylate transporters (MCTs) in the retina, in which MCT1 is expressed by photoreceptors and MCT4 expression is specific to M?ller glial cells, the primary glial cell that supports photoreceptor function in multiple ways. The hypothesis is also supported by the severe retinal phenotype of mice lacking CD147, an accessory protein that is required for normal MCT1 expression. We will use systemic and conditional mouse models for MCT1, MCT4, and CD147 to define the role of lactate and its transport by MCTs in support of retinal energy metabolism. This project is comprised of two Specific Aims.
Aim 1 will characterize the retina of a newly established Mct4 mutant mouse, using visual electrophysiological, anatomical and biochemical approaches.
Aim 2 will apply these same techniques to Mct1 mutant mice. First we will compare the retinal phenotype of Mct1+/-heterozygotes with that of wild type littermates. Since the Mct1 knock-out does not survive, we will eliminate Mct1 expression in rod and/or cone photoreceptors by cell-specific deletion of CD147. At the completion of this project, we will understand the role that MCT1 and MCT4 play in supporting metabolism and survival of rod and cone photoreceptors. We will know whether M?ller glial cells are an important source of retinal lactate and whether lactate is an important source of energy for rod and/or cone photoreceptor metabolism. This research will provide important insights into outer retinal metabolism and will provide a framework for understanding diseases of the outer retina.
Retinal photoreceptors have high demands for energy to maintain normal vision. Glucose is the ultimate source for this energy, but photoreceptors may not use glucose directly. Instead, a supportive glial cell, the Muller glial cell, may convert glucose to lactate, which is then release through a specialized transporter. Extracellular lactate is then taken up by another transporter and used to support function of rod and cone photoreceptors. A similar metabolic coupling has been established in other tissues, and the purpose of this project is to determine whether this plays an important role in supporting retinal function. We will examine mice lacking a specific transporter, and determine the impact of this change on the outer retina. At the completion of this project, we will better understand retinal metabolism, abnormalities in which contribute to visual diseases that afflict the veteran population.